EP1888578B9 - 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoléin-3-yl-2,3-dihydro-imidazo [4,5-c] quinoléinyl)-phenyl]propionitrile en tant qu'inhibiteur de kinase lipidique - Google Patents

2-methyl-2-[4-(3-methyl-2-oxo-8-quinoléin-3-yl-2,3-dihydro-imidazo [4,5-c] quinoléinyl)-phenyl]propionitrile en tant qu'inhibiteur de kinase lipidique Download PDF

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EP1888578B9
EP1888578B9 EP06753710A EP06753710A EP1888578B9 EP 1888578 B9 EP1888578 B9 EP 1888578B9 EP 06753710 A EP06753710 A EP 06753710A EP 06753710 A EP06753710 A EP 06753710A EP 1888578 B9 EP1888578 B9 EP 1888578B9
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Prior art keywords
methyl
quinolin
phenyl
imidazo
dihydro
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EP1888578B8 (fr
EP1888578A2 (fr
EP1888578B1 (fr
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Carlos Garcia-Echeverria
Frédéric STAUFFER
Pascal Furet
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Novartis AG
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Novartis AG
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Priority to DK10175375.4T priority Critical patent/DK2270008T3/da
Priority to PL06753710T priority patent/PL1888578T3/pl
Priority to EP10175375A priority patent/EP2270008B8/fr
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Priority to EP10175369A priority patent/EP2292617B1/fr
Priority to DK10175369.7T priority patent/DK2292617T3/da
Priority to SI200631230T priority patent/SI1888578T1/sl
Priority to PL10175375T priority patent/PL2270008T3/pl
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present disclosure relates to novel organic compounds, processes for the preparation thereof, the compounds for use in the treatment of the human or animal body, the compounds for use alone or in combination with one or more other pharmaceutically active compounds in the treatment of an inflammatory or obstructive airway disease, such as asthma, disorders commonly occurring in connection with transplantation, or a proliferative disease, such as a tumor disease, which may be solid or liquid; and such a compound for use alone or in combination with one or more other pharmaceutically active compounds - for the manufacture of a pharmaceutical preparation for the treatment of said diseases.
  • WO03/097641 discloses certain 1H-Imidazo[4,5-c]quinoline derivatives and uses thereof in the treatment of protein kinase inhibitors.
  • R 1 is naphthyl or phenyl wherein said phenyl is substituted by one or two substituents independently selected from the group consisting of Halogen; lower alkyl-unsubstituted or substituted by halogen, cyano, imidazolyl or triazolyl; cycloalkyl; amino substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkyl sulfonyl, lower alkoxy and lower alkoxy lower alkylamino; piperazinyl unsubstituted or substituted by one or two substituents independently selected from the group consisting of lower alkyl and lower alkyl sulfonyl; 2-oxo-pyrrolidinyl; lower alkoxy lower alkyl; imidazolyl; pyrazolyl; and triazolyl; R 2 is O or S; R 3 is lower alkyl; R 4 is pyridy
  • the prefix “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.
  • alkyl has up to a maximum of 12 carbon atoms and is especially lower alkyl.
  • Lower alkyl is preferably alkyl with from and including 1 up to and including 7, preferably from and including 1 to and including 4, and is linear or branched; preferably, lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or preferably methyl.
  • Cycloalkyl is preferably cycloalkyl with from and including 3 up to and including 6 carbon atoms in the ring; cycloalkyl is preferably cyclopropyl, cyclobutyl , cyclopently or cyclohexyl.
  • Alkyl which is substituted by halogen is preferably perfluoro alkyl such as trifluoromethyl.
  • Halogen is especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.
  • any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
  • Salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts.
  • Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, malonic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1
  • salts for isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates.
  • pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
  • R1 is preferably phenyl wherein said phenyl is substituted by one or two substituents independently selected from the group consisting of Halogen; lower alkyl substituted by halogen, cyano, imidazolyl or triazolyl; amino substituted by one or two substituents independently selected from the group consisting of lower alkyl and lower alkyl sulfonyl; piperazinyl wherein said piperazinyl is unsubstituted or substituted by one or two lower alkyl substituents; imidazolyl; pyrazolyl; and triazolyl.
  • R2 is preferably O.
  • R3 is preferably Me.
  • R4 is preferably pyrimidinyl or pyridyl unsubstituted or substituted by halogen, cyano, lower alkyl, lower alkoxy or piperazinyl unsubstituted or substituted by lower alkyl; quinolinyl unsubstituted or substituted by halogen; quinoxalinyl; or phenyl substituted with alkoxy.
  • R5 is preferably hydrogen.
  • n is preferably 0.
  • R 7 is preferably hydrogen.
  • the compound in accordance with the present invention is 2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile;
  • the compounds of formula I have advantageous pharmacological properties and inhibit the activity of the lipid kinases, such as the PI3-kinase and/or members of the PI3-kinase-related protein kinase family (also called PIKK and include DNA-PK, ATM, ATR, hSMG-1 and mTOR), such as the DNA protein-kinase, and may be used to treat disease or disorders which depend on the activity of said kinases.
  • the lipid kinases such as the PI3-kinase and/or members of the PI3-kinase-related protein kinase family (also called PIKK and include DNA-PK, ATM, ATR, hSMG-1 and mTOR), such as the DNA protein-kinase.
  • compounds of formula (I) in free or pharmaceutically acceptable salt form are useful in the treatment of conditions which are mediated by the activation of the PI3 kinase enzymes, such as proliferative, inflammatory or allergic conditions, or disorders commonly occurring in connection with transplantation.
  • the compounds in accordance with the invention are for use in symptomatic or prophylactic treatment.
  • Other diseases include Cow
  • the compounds according to the invention are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodelling or disease progression.
  • Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g.
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory.
  • Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
  • the present invention provides the compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile for use in the treatment of other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable and include acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • ALI acute lung injury
  • ARDS adult/acute respiratory distress syndrome
  • COAD chronic obstructive pulmonary, airways or lung disease
  • COAD chronic obstructive pulmonary, airways or lung disease
  • COAD chronic ob
  • the present invention also provides the compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile for use in the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis anthracosis
  • asbestosis chalicosis
  • ptilosis ptilosis
  • siderosis silicosis
  • tabacosis tabacosis and byssinosis.
  • the present invention provides the compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile is for use in the treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related disorders of the airways (e.g.
  • eosinophilic infiltration of pulmonary tissues including hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil-related disorders of the airways consequential or concomitant to Löffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.
  • the present invention provides the compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile for use in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.
  • inflammatory or allergic conditions of the skin for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythem
  • the present invention provides the compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyll-propionitrile for use in the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or aetiology, including autoimmune haematological disorders (e.g.
  • haemolytic anaemia haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease endocrine opthalmopathy
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary billiary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy).
  • the invention provides the use of-2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile, or a pharmaceutically acceptable salt, thereof for the preparation of a medicament for the treatment of a proliferative disease, an inflammatory disease or an obstructive respiratory disease, or a disorder commonly occurring in connection with transplantation.
  • the kinase reaction was performed in a final volume of 50 ⁇ L per well of a half area COSTAR, 96 well plate.
  • the final concentrations of ATP and phosphatidyl inositol in the assay were 5 ⁇ M and 6 ⁇ g/mL respectively.
  • the reaction was started by the addition of PI3 kinase p110 ⁇ .
  • the components of the assay were added per well as follows:
  • Some of the compounds show a certain level of selectivity against the different paralogs PI3K alpha, gamma and delta.
  • DNA-PK is a nuclear serine/threonine protein kinase that requires double-stranded DNA (dsDNA) for activity.
  • dsDNA double-stranded DNA
  • DNA-PK X5 reaction buffer 250 mM HEPES, 500 mM KCI, 50 mM MgCl 2 , 1 mM EGTA, 0.5 mM EDTA, 5 mM DTT, pH to 7.5 with KOH
  • the activation buffer was made of 100 ⁇ g/ml of calf thymus DNA in control buffer (10 mM Tris-HCl (pH 7.4), 1 mM EDTA (pH 8.0)).
  • termination buffer 7.5 M guanidine hydrochloride
  • the medium is quickly removed by aspiration and the cells rinsed twice with precooled PBS. Cells are then placed on ice and immediately lysed. Protein samples are then resolved by SDS-PAGE and transferred to lmmbilon-P membrane for detection of levels of endogenous GSK3 ⁇ , PKB, PhosphoT308-PKB and PhosphoS9-GSK3 ⁇ by western-blotting. Membranes are then dried and covered with polyethylene film, and chemiluminescence measured in a MultilmageTM Light Cabinet (Alpha Innotech Corp) driven with the FluorChemTM software (Alpha Innotech Corp).
  • the data are analyzed with AlphaEasy software, plotted as % of control (cells treated with DMSO in identical experimental conditions used for kinase inhibitors) with SigmaPlot ® (SSPI Inc, version 7) as a regression curve (Four Parameter Logistic Cubic) and IC 50 values are determined accordingly.
  • mice with s.c. transplanted human glioblastoms U87MG tumors can be used to determine the anti-tumor activity of PI3 kinase inhibitors.
  • a tumor fragment of approximately 25 mg is placed under the skin on the animals' left flank and the small incised wound is closed by means of suture clips.
  • tumors reaches a volume of 100 mm 3 the mice are divided at random into groups of 6-8 animals and treatment commences.
  • the treatment is carried out for a 2-3 weeks period with peroral, intravenous or intra-peritoneal administration once daily (or less frequently) of a compound of formula (I) in a suitable vehicle at defined doses.
  • the tumors are measured twice a week with a slide gauge and the volume of the tumors is calculated.
  • cell line U87MG As an alternative to cell line U87MG, other cell lines may also be used in the same manner, for example,
  • Compounds of the present disclosure exhibit T cell inhibiting activity. More particular the compounds of the invention prevent T cell activation and/or proliferation in e.g. aqueous solution, e.g. as demonstrated in accordance with the following test method.
  • the two-way MLR is performed according to standard procedures ( J. Immunol. Methods, 1973, 2, 279 and Meo T. et al., Immunological Methods, New York, Academic Press, 1979, 227-39 ).
  • spleen cells from CBA and BALB/c mice (1.6 x 105 cells from each strain per well in flat bottom tissue culture microtiter plates, 3.2 x 105 in total) are incubated in RPMI medium containing 10% FCS, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin (Gibco BRL, Basel, Switzerland), 50 ⁇ M 2-mercaptoethanol (Fluka, Buchs, Switzerland) and serially diluted compounds. Seven threefold dilution steps in duplicates per test compound are performed. After four days of incubation 1 ⁇ Ci 3H-thymidine is added.
  • the compounds of the invention have IC50 values in the range of 1 nM to 10 ⁇ M, preferably from 10 nM to 100 nM.
  • a compound of the formula (I) may also be used to advantage in combination with other antiproliferative compounds.
  • antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms;
  • aromatase inhibitor as used herein relates to a compound which inhibits the estrogen production, i.e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane can be administered, e.g., in the form as it is marketed, e.g.
  • Formestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark LENTARON.
  • Fadrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark AFEMA.
  • Anastrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark ARIMIDEX.
  • Letrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR.
  • Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g.
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g. breast tumors.
  • antiestrogen as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be administered, e.g., in the form as it is marketed, e.g. under the trademark NOLVADEX.
  • Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under the trademark EVISTA.
  • Fulvestrant can be formulated as disclosed in US 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g. under the trademark FASLODEX.
  • a combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g. breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g. as disclosed in US 4,636,505 .
  • bicalutamide CASODEX
  • gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin is disclosed in US 4,100,274 and can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZOLADEX.
  • Abarelix can be formulated, e.g. as disclosed in US 5,843,901 .
  • topoisomerase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO99/ 17804 ).
  • Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark CAMPTOSAR.
  • Topotecan can be administered, e.g., in the form as it is marketed, e.g. under the trademark HYCAMTIN.
  • topoisomerase II inhibitor includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, e.g. CAELYX), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide can be administered, e.g. in the form as it is marketed, e.g. under the trademark ETOPOPHOS.
  • Teniposide can be administered, e.g. in the form as it is marketed, e.g.
  • Doxorubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN.
  • Epirubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark FARMORUBICIN.
  • Idarubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZAVEDOS.
  • Mitoxantrone can be administered, e.g. in the form as it is marketed, e.g. under the trademark NOVANTRON.
  • microtubule active agent relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, e.g. paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine, discodermolides, cochicine and epothilones and derivatives thereof, e.g. epothilone B or D or derivatives thereof.
  • Paclitaxel may be administered e.g. in the form as it is marketed, e.g. TAXOL.
  • Docetaxel can be administered, e.g., in the form as it is marketed, e.g. under the trademark TAXOTERE.
  • Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark VINBLASTIN R.P..
  • Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark FARMISTIN.
  • Discodermolide can be obtained, e.g., as disclosed in US 5,010,099 .
  • Epothilone derivatives which are disclosed in WO 98/10121 , US 6,194,181 , WO 98/25929 , WO 98/08849 , WO 99/43653 , WO 98/22461 and WO 00/31247 .
  • Epothilone A and/or B are especially preferred.
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark CYCLOSTIN.
  • Ifosfamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark HOLOXAN.
  • histone deacetylase inhibitors or “HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity.
  • SAHA Suberoylanilide hydroxamic acid
  • antimetabolite includes, but is not limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.
  • Capecitabine can be administered, e.g., in the form as it is marketed, e.g. under the trademark XELODA.
  • Gemcitabine can be administered, e.g., in the form as it is marketed, e.g. under the trademark GEMZAR..
  • platinum compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark CARBOPLAT.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATIN.
  • compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g.,
  • anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (THALOMID) and TNP-470.
  • TAALOMID thalidomide
  • TNP-470 TNP-470.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, e.g. okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes are e.g. retinoic acid, ⁇ - ⁇ - or ⁇ -tocopherol or ⁇ - ⁇ - or ⁇ -tocotrienol.
  • cyclooxygenase inhibitor as used herein includes, but is not limited to, e.g. Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, e.g. 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • bisphosphonates as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark DIDRONEL.
  • Clodronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONEFOS.
  • titaniumudronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark SKELID.
  • “Pamidronic acid” can be administered, e.g. in the form as it is marketed, e.g. under the trademark AREDIATM.
  • “Alendronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX.
  • “Ibandronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONDRANAT.
  • “Risedronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark ACTONEL.
  • "Zoledronic acid” can be administered, e.g. in the form as it is marketed, e.g.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (CerticanTM), CCl-779 and ABT578.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation.
  • the term includes, but is not limited to, PI-88.
  • biological response modifier refers to a lymphokine or interferons, e.g. interferon ⁇ .
  • inhibitor of Ras oncogenic isoforms e.g. H-Ras, K-Ras, or N-Ras
  • H-Ras, K-Ras, or N-Ras refers to compounds which target, decrease or inhibit the oncogenic activity of Ras e.g. a "farnesyl transferase inhibitor” e.g. L-744832, DK8G557 or R115777 (Zarnestra).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase.
  • Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, e.g. telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine aminopeptidase are e.g. bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include e.g. Bortezomid (VelcadeTM)and MLN 341.
  • matrix metalloproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MM1270B or AAJ996.
  • MMP matrix metalloproteinase inhibitor
  • FMS-like tyrosine kinase inhibitors e.g. compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors e.g. compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, e.g. PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90 e.g., 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HerceptinTM), Trastuzumab-DM1,erbitux, bevacizumab (AvastinTM), rituximab (Rituxan ® ), PRO64553 (anti-CD40) and 2C4 Antibody.
  • trastuzumab HerceptinTM
  • Trastuzumab-DM1,erbitux bevacizumab
  • AvastinTM bevacizumab
  • rituximab Renuxan ®
  • PRO64553 anti-CD40
  • compounds of formula (I) can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds of formula (I) can be administered in combination with, e.g., farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • antigenemic compounds includes, for example, Ara-C, a pyrimidine analog, which is the 2'-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.
  • HDAC histone deacetylase
  • SAHA suberoylanilide hydroxamic acid
  • HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 , in particular, N -hydroxy-3-[4-[[[2-(2-methyl-1 H -indol-3-yl)-ethyl]-amino]methyl]phenyl]-2 E -2-propenamide, or a pharmaceutically acceptable salt thereof and N -hydroxy-3-[4-[(2-hydroxyethyl) ⁇ 2-(1 H -indol-3-yl)ethyl ⁇ -amino]methyl]phenyl]-2 E -2-propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt.
  • Somatostatin receptor antagonists as used herein refers to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230.
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • ionizing radiation means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1, pp. 248-275 (1993 ).
  • EDG binders refers a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • ribonucleotide reductase inhibitors refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • ara-C cytosine arabinoside
  • 6-thioguanine 5-fluorouracil
  • cladribine 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1 H -isoindole-1,3-dione derivatives, such as PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned in Nandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994 ).
  • S-adenosylmethionine decarboxylase inhibitors includes, but is not limited to the compounds disclosed in US 5,461,076 .
  • VEGF vascular endothelial growth factor
  • WO 98/35958 e.g. 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, e.g. the succinate, or in WO 00/09495 , WO 00/27820 , WO 00/59509 , WO 98/11223 , WO 00/27819 and EP 0 769 947 ; those as described by Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218 (1999 ); Yuan et al., Proc Natl Acad Sci U S A, Vol.
  • anthranilic acid amides ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, e.g. rhuMAb and RHUFab, VEGF aptamer e.g. Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibody, Angiozyme (RPI 4610) and Bevacizumab (AvastinTM).
  • Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers.
  • Examples of photodynamic therapy includes treatment with compounds, such as e.g. VISUDYNE and porfimer sodium.
  • Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11- ⁇ -epihydrocotisol, cortexolone, 17 ⁇ -hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Implants containing corticosteroids refers to compounds, such as e.g. fluocinolone, dexamethasone.
  • chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • the compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • a compound of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • the invention includes a combination of a compound of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said compound of the invention and said drug substance being in the same or different pharmaceutical composition.
  • Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167 , WO 02/12266 , WO 02/100879 , WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/035668 , WO 03/048181 , WO 03/062259 , WO 03/064445 , WO 03/072592 , non-steroidal glucocorticoid receptor agonists such as those described in WO 00/00531 , WO 02/10143 , WO 03/082280 , WO 03/082787 , WO 03/104195 , WO 04/005229 ; LTB4 antagonists
  • Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in WO 01/04118 , WO 02/51841 , WO 02/53564 , WO 03/00840 , WO 03/87094 , WO 04/05285 , WO 02/00652 , WO 03/53966 , EP 424021 , US 5171744 , US 3714357 , WO 03/33495 and WO 04/018422 .
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine as well as those disclosed in WO 03/099807 , WO 04/026841 and JP 2004107299 .
  • chemokine receptors e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists such as N-[[4-[[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-amin-ium chloride (TAK-770), and CCR-5 antagonists described in US 6166037 (particularly claims 18 and 19), WO 00/66558 (particularly claim 8), WO 00
  • a compound of the formula (I) may also be used to advantage in combination with known therapeutic processes, for example, the administration of hormones or especially radiation.
  • a compound of formula (I) may in particular be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • ком ⁇ онент there is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the formula (I) and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g. synergistic effect.
  • the invention also provides a pharmaceutical preparation, comprising the compound2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile, or a pharmaceutically acceptable salt of such a compound, and at least one pharmaceutically acceptable carrier.
  • the compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.
  • a compound of formula I can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
  • the dosage of the active ingredient depends upon a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed.
  • a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • the dose of the compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile or a pharmaceutically acceptable salt thereof to be administered to warm-blooded animals, for example humans of approximately 70 kg body weight, is preferably from approximately 3 mg to approximately 5 g, more preferably from approximately 10 mg to approximately 1.5 g, most preferably from about 100 mg to about 1000 mg per person per day, divided preferably into 1 to 3 single doses which may, for example, be of the same size. Usually, children receive half of the adult dose.
  • the compounds of the invention may be administered by any conventional route, in particular parenterally, for example in the form of injectable solutions or suspensions, enterally, e.g. orally, for example in the form of tablets or capsules, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form.
  • Topical administration is e.g. to the skin.
  • a further form of topical administration is to the eye.
  • Pharmaceutical compositions comprising a compound of the invention in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.
  • the invention relates also to pharmaceutical compositions comprising an effective amount, especially an amount effective in the treatment of one of the above-mentioned disorders, of the compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile together with pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral administration and that may be inorganic or organic, solid or liquid.
  • tablets or gelatin capsules that comprise the active ingredient together with diluents, for example lactose, dextrose, mannitol, and/or glycerol, and/or lubricants and/or polyethylene glycol.
  • Tablets may also comprise binders, for example magnesium aluminum silicate, starches, such as com, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners.
  • diluents for example lactose, dextrose, mannitol, and/or glycerol, and/or lubricants and/or polyethylene glycol.
  • Tablets may also comprise binders, for example magnesium aluminum silicate,
  • the pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilisers, wetting compounds and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.
  • the present pharmaceutical compositions which may, if desired, comprise other pharmacologically active substances are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes, and comprise approximately from 1% to 99%, especially from approximately 1% to approximately 20%, active ingredient(s).
  • the present invention provides the compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile, or a pharmaceutically acceptable salt of such a compound, for use in a method for the treatment of the human or animal body.
  • the present invention also relates to the use of the compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile, or a pharmaceutically acceptable salt of such a compound, for the preparation of a medicament for the treatment of a proliferative disease, an inflammatory disease, or an obstructive airway disease, or disorders commonly occurring in connection with transplantation.
  • the invention relates to a pharmaceutical composition for use in the treatment of solid or liquid tumours in warm-blooded animals, including humans, comprising an antitumourally effective dose of the compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile or a pharmaceutically acceptable salt of such a compound together with a pharmaceutical carrier.
  • the present disclosure also relates to a process for the preparation of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that a imidazoquinoline derivative of the formula II
  • the compound of the invention may be prepared by processes that, though not applied hitherto for the new compounds of the present invention, are known per se , especially by a process characterized in that for the synthesis of a compound of the formula I wherein the symbols R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are as defined for a compound of the formula I, a compound of the formula II wherein R 1 , R 2 , R 3 , R 5 , R 6 and n are as defined for a compound of the formula I is reacted with a boronic acid of the formula III R 4 -B(OH) 2 (III) or of formula IIIa wherein R 4 is as defined for a compound of the formula I in the presence of a base and a catalyst in a suitable solvent; where the above starting compounds II and III may also be present with functional groups in protected form if necessary and/or in the form of salts, provided a salt-forming group is present and the reaction in salt form is possible; any protecting groups in
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are as defined for compounds of formula I, unless otherwise indicated.
  • the reaction of compound of formula II and III is preferably carried out under the conditions of a Suzuki-reaction, preferably in a mixture of a polar aprotic solvent such as DMF and water in the presence of a catalyst, especially a noble metal catalyst, such as palladium (II), preferable bis(triphenylphosphine)palladium (II) dichloride; in the presence of a base such as potassium carbonate.
  • a catalyst especially a noble metal catalyst, such as palladium (II), preferable bis(triphenylphosphine)palladium (II) dichloride
  • a base such as potassium carbonate.
  • one or more other functional groups for example carboxy, hydroxy, amino, or mercapto, are or need to be protected in a compound of formulae II or III, because they should not take part in the reaction, these are such groups as are usually used in the synthesis of peptide compounds, and also of cephalosporins and penicillins, as well as nucleic acid derivatives and sugars.
  • the protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by acetolysis, protonolysis, solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products.
  • the specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter.
  • functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned hereinabove under "protecting groups".
  • the protecting groups are then wholly or partly removed according to one of the methods described there.
  • Salts of a compound of formula I with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of formula I may thus be obtained by treatment with an acid or with a suitable anion exchange reagent.
  • a salt with two acid molecules for example a dihalogenide of a compound of formula I
  • Salts can usually be converted to free compounds, e.g. by treating with suitable basic compounds, for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • suitable basic compounds for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • Stereoisomeric mixtures e.g. mixtures of diastereomers
  • Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This separation may take place either at the level of a starting compound or in a compound of formula I itself.
  • Enantiomers may be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands.
  • a compound of the formula I, wherein R 2 is O, can be converted into the respective compound wherein R 2 is S, for example, by using an appropriate sulfur compound, e.g. using reaction with Lawesson's reagent (2,4-bis-(4-methoxyphenyl)2,4-dithioxo-1,2,3,4-dithiaphosphetan) in an appropriate solvent such as dioxane.
  • an appropriate sulfur compound e.g. using reaction with Lawesson's reagent (2,4-bis-(4-methoxyphenyl)2,4-dithioxo-1,2,3,4-dithiaphosphetan) in an appropriate solvent such as dioxane.
  • All process steps described here can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralising agents, for example ion exchangers, typically cation exchangers, for example in the H + form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from -100°C to about 190°C, preferably from about -80°C to about 150°C, for example at -80 to -60°C, at room temperature, at - 20 to 40°C or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen.
  • solvents or diluents preferably such as are inert to the reagents used
  • Salts may be present in all starting compounds and transients, if these contain salt-forming groups. Salts may also be present during the reaction of such compounds, provided the reaction is not thereby disturbed.
  • isomeric mixtures that occur can be separated into their individual isomers, e.g. diastereomers or enantiomers, or into any mixtures of isomers, e.g. racemates or diastereomeric mixtures, typically as described under "Additional process steps”.
  • the solvents from which those can be selected which are suitable for the reaction in question include for example water, esters, typically lower alkyl-lower alkanoates, e.g ethyl acetate, ethers, typically aliphatic ethers, e.g. diethylether, or cyclic ethers, e.g.
  • tetrahydrofuran liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically methanol, ethanol or 1- or 2-propanol, 1-butanol, nitriles, typically acetonitrile, halogenated hydrocarbons, typically dichloromethane, acid amides, typically dimethylformamide, bases, typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic acids, typically lower alkanecarboxylic acids, e.g. acetic acid, carboxylic acid anhydrides, typically lower alkane acid anhydrides, e.g.
  • acetic anhydride cyclic, linear, or branched hydrocarbons, typically cyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g. aqueous solutions, unless otherwise stated in the description of the process.
  • solvent mixtures may also be used in processing, for example through chromatography or distribution.
  • the compounds of formula I are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization (present as solvates).
  • a compound of formula I is prepared according to or in analogy to the processes and process steps defined in the Examples.
  • New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention.
  • such starting materials are used and reaction conditions so selected as to enable the preferred compounds to be obtained.
  • a compound of the formula II, wherein n is 0, can be prepared by the alkylation of an amino compound of the formula IV, wherein R 1 , R 2 and R 5 have the meanings as given under formula I with a compound of the formula V R 3 - X (V) wherein R 3 has the meaning as given under formula I and X is halogen or another suitable leaving group, in the presence of a base, e.g. sodium hydroxide, in a suitable solvent, e.g. a mixture of dichloromethane and water, preferably in the presence of a phase transfer catalyst, e.g. tetrabutylammonium bromide, at a temperature between 0 °C and 50 °C, preferably at room temperature.
  • a base e.g. sodium hydroxide
  • a suitable solvent e.g. a mixture of dichloromethane and water
  • a phase transfer catalyst e.g. tetrabutylammonium bromide
  • a compound of the formula II, wherein n is 0, can be converted into the respective compound wherein n is 1, for example, by using an appropriate oxidant, e.g. using reaction with meta-chloroperbenzoic acid in an appropriate solvent such as dichloromethan at room temperature.
  • an appropriate oxidant e.g. using reaction with meta-chloroperbenzoic acid in an appropriate solvent such as dichloromethan at room temperature.
  • a compound of the formula IV, wherein R 2 is O, can be prepared by the cyclisation of a diamino compound of the formula VI, wherein R 1 and R 5 have the meanings as given under formula I with trichloromethyl chloroformate in the presence of a base, such as triethylamine in an appropriate solvent, such as dichloromethane.
  • a compound of the formula VI can be prepared by the reduction of a nitro compound of the formula VII, wherein R 1 and R 5 have the meanings as given under formula I.
  • the reduction preferably takes place in the presence of a suitable reducing agent, such as hydrogen in the presence of an appropriate catalyst, such as Raney nickel under pressure, e.g. between 1.1 and 2 bar, in an appropriate solvent, e.g. an alcohol or ether, such as methanol or tetrahydrofurane or a mixture thereof.
  • a suitable reducing agent such as hydrogen
  • an appropriate catalyst such as Raney nickel under pressure, e.g. between 1.1 and 2 bar
  • an appropriate solvent e.g. an alcohol or ether, such as methanol or tetrahydrofurane or a mixture thereof.
  • the reaction temperature is preferably between 0 and 80 °C, especially 15 to 30 °C.
  • a compound of the formula VII can be prepared by reaction of a compound VIII wherein R 5 is as defined for a compound of the formula I and Y is halogen or another suitable leaving group, is reacted with a compound of the formula IX, R 1 - NH 2 (IX) wherein R 1 is as defined for a compound of the formula I, at a temperature between 0 °C and 50 °C, preferably at room temperature in a suitable solvent, i.e. acetic acid.
  • Example 1i The following compounds (Table 1) are prepared in a similar manner as described in example 1 by reacting 2-[4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile (Example 1i ), with the appropriate boronic acid :
  • Example 2 3-pyridineboronic acid (Aldrich, Buchs, Switzerland),
  • Example 3 4-methoxy-3-pyridylboronic acid (Frontier Scientific, Logan, USA),
  • Example 4 3-methoxypyridine-5-boronic acid pinecol ester (Frontier Scientific, Logan, USA)
  • Example 5 4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (CB Research & Development, New Castle, USA)
  • Example 2 The following compounds (Table 2) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c) with 2-(4-aminophenyl)-2-ethyl-butyronitrile (Example 12a), and with the appropriate boronic acid: Table 2 Example Compound name ES-MS (M + H) + t ret [min] 12 2-Ethyl-2-[4-(3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-butyronitrile 448 2.69 Grad 1 13 2-Ethyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-butyronitrile 498 3.13 Grad 1
  • Example 1d The title compound is prepared in a similar manner as described in Example 1e using iodoethane (Fluka, Buchs, Switzerland) in Example 1d .
  • Title compound: ES-MS: 189 (M + H) + , Br pattern; analytical HPLC: t ret 2.50 min (Grad 1).
  • Example 3 The following compounds (Table 3) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 1-(4-amino-2-fluoro-phenyl)-pyrrolidin-2-one (Example 14a ), and with the appropriate boronic acid: Table 3 Example Compound name ES-MS (M + H) + t ret [min] 14 1-[3-Fluoro-4-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 454 2.26 Grad 1 15 1-[3-Fluoro-4-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one
  • Example 4 The following compounds (Table 4) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 1-(4-aminophenyl)-pyrrolidin-2-one (Example 16a ), and with the appropriate boronic acid: Table 4 Example Compound name ES-MS (M + H) + t ret [min] 16 3-Methyl-1-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 436 2.24 Grad 1 17 3-Methyl-1-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 486 2.61 Grad 1
  • Example 5 The following compounds (Table 5) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 2-fluoro-N1,N1-bis-(2-methoxy-ethyl)-benzene-1,4-diamine (Example 18a ), and with the appropriate boronic acid: Table 5
  • Grad 1 19 1- ⁇ 4-[Bis-(2-methoxy-ethyl)-amino]-3-fluoro-phenyl ⁇ -3-methyl-8-quinolin-3-yl-1,3-d
  • Example 18b The title compound is obtained in a similar manner as described in Example 14a starting with (2-fluoro-4-nitro-phenyl)-bis-(2-methoxy-ethyl)-amine (Example 18b ).
  • Title compound: ES-MS: 243 (M+H) + ; analytical HPLC: t ret 1.98 minutes (Grad 1).
  • Example 6 The following compounds (Table 6) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with N,N-bis-(2-methoxy-ethyl)-benzene-1,4-diamine (Example 20a ), and with the appropriate boronic acid: Table 6 Example Compound name ES-MS (M + H) + t ret [min] 20 1- ⁇ 4-[Bis-(2-methoxy-ethyl)-amino]-phenyl ⁇ -3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 484 2.50 Grad 1 21 1- ⁇ 4-[Bis-(2-methoxy-ethyl)-amino]-phenyl ⁇ -3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 5
  • Example 7 The following compounds (Table 7) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 2-naphthylamine (Aldrich, Buchs, Switzerland), and with the appropriate boronic acid: Table 7 Example Compound name ES-MS (M + H) + t ret [min] 22 3-Methyl-1-naphthalen-2-yl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 403 2.53 Grad 1 23 3-Methyl-1-naphthalen-2-yl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 453 3.02 Grad 1
  • Example 8 The following compounds (Table 8) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 2-chloroaniline (Fluka, Buchs, Switzerland), and with the appropriate boronic acid: Table 8 Example Compound name ES-MS (M + H) + t ret [min] 24 1-(2-Chloro-phenyl)-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 387 2.32 Grad 1 25 1-(2-Chloro-phenyl)-3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 437 2.83 Grad 1
  • Example 9 The following compounds (Table 9) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 2-toluidine (Fluka, Buchs, Switzerland), and with the appropriate boronic acid: Table 9 Example Compound name ES-MS (M + H) + t ret [min] 26 3-Methyl-8-pyridin-3-yl-1-o-tolyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 367 2.27 Grad 1 27 3-Methyl-8-quinolin-3-yl-1-o-tolyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 417 2.79 Grad 1
  • Example 10 The following compounds (Table 10) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 2-ethylaniline (Aldrich, Buchs, Switzerland), and with the appropriate boronic acid: Table 10 Example Compound name ES-MS (M + H) + t ret [min] 28 1-(2-Ethyl-phenyl)-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 381 2.40 Grad 1 29 1-(2-Ethyl-phenyl)-3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 431 2.93 Grad 1
  • Example 11 The following compounds (Table 11) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 2-trifluoromethylaniline (Fluka, Buchs, Switzerland), and with the appropriate boronic acid: Table 11 Example Compound name ES-MS (M + H) + t ret [min] 30 3-Methyl-8-pyridin-3-yl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 421 2.43 Grad 1 31 3-Methyl-8-quinolin-3-yl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 471 2.91 Grad 1
  • Example 12 The following compounds (Table 12) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 4-fluoro-2-methylaniline (Aldrich, Buchs, Switzerland), and with the appropriate boronic acid: Table 12 Example Compound name ES-MS (M + H) + t ret [min] 32 1-(4-Fluoro-2-methyl-phenyl)-3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 385 2.30 Grad 1 33 1-(4-Fluoro-2-methyl-phenyl)-3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 435 2.85 Grad 1
  • Example 13 The following compounds (Table 13) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 2-chloro-4-fluoroaniline (Aldrich, Buchs, Switzerland), and with the appropriate boronic acid: Table 13 Example Compound name ES-MS (M + H) + t ret [min] 34 1-(2-Chloro-4-fluoro-phenyl)-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 405 2.37 Grad 1 35 1-(2-Chloro-4-fluoro-phenyl)-3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 455 2.89 Grad 1
  • Example 14 The following compounds (Table 14 ) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 3-chloroaniline (Fluka, Buchs, Switzerland), and with the appropriate boronic acid: Table 14 Example Compound name ES-MS (M + H) + t ret [min] 36 1-(3-Chloro-phenyl)-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 387 2.37 Grad 1 37 1-(3-Chloro-phenyl)-3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 437 2.89 Grad 1
  • Example 15 The following compounds (Table 15) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 3-trifluoromethylaniline (Fluka, Buchs, Switzerland), and with the appropriate boronic acid: Table 15 Example Compound name ES-MS (M + H) + t ret [min] 38 3-Methyl-8-pyridin-3-yl-1-(3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 421 2.53 Grad 1 39 3-Methyl-8-quinolin-3-yl-1-(3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 471 3.02 Grad 1
  • Example 16 The following compounds (Table 16) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 4-methoxymethylaniline (Example 38a), and with the appropriate boronic acid: Table 16 Example Compound name ES-MS (M + H) + t ret [min] 40 1-(4-Methoxymethyl-phenyl)-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 2.28 397 Grad 1 41 1-(4-Methoxymethyl-phenyl)-3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 2.75 447 Grad 1
  • Example 17 The following compounds (Table 17) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 2-chloro-4-(2-methoxy-ethyl)-phenylamine (Example 42a ), and with the appropriate boronic acid: Table 17 Example Compound name ES-MS (M + H) + t ret [min] 42 1-[2-Chloro-4-(2-methoxy-ethyl)-phenyl]-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5- c ]quinolin-2-one 2.53 445 Grad 1 43 1-[2-Chloro-4-(2-methoxy-ethyl)-phenyl]-3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 2.99 495 Grad 1
  • Example 18 The following compounds (Table 18) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with 4-(2-methoxyethyl)-phenylamine (Example 42b ), and with the appropriate boronic acid: Table 18 Example Compound name ES-MS (M + H) + t ret [min] 44 1-[4-(2-Methoxy-ethyl)-phenyl]-3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 2.37 411 Grad 1 45 1-[4-(2-Methoxy-ethyl)-phenyl]-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one 2.83 461 Grad 1
  • Example 20 The following compounds (Table 20) are prepared in a similar manner as described in Example 1 using 6-bromo-4-chloro-7-fluoro-3-nitro-quinoline (Example 48a ), and the required boronic acid: Table 20 Example Compound name ES-MS (M + H) + t ret [min] 48 2-[4-(7-Fluoro-3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydro-imidazo[4,5- c ]quinolin-1-yl)-phenyl]-2-methyl-propionitrile 438 2.54 Grad 1 49 2-[4-(7-Fluoro-3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5- c ]quinolin-1-yl)-phenyl]-2-methyl-propionitrile 488 3.03 Grad 1
  • Example 50a 62 mg (0.128 mmol) of methyl-[4-(3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-carbamic acid tert-butyl ester (Example 50a ) is treated with 2.5 ml of 1 M HCl in dioxane at rt for 1 h, and then the solution is evaporated to dryness. The residue is taken in 2 ml of CH 2 Cl 2 together with 414 ⁇ l (5.13 mmol) of pyridine and 66 mg (0.579 mmol) of mesylchloride (Fluka, Buchs, Switzerland).
  • Example 1c The title compound is prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c ) with (4-amino-phenyl)-carbamic acid tert-butyl ester (Fluka, Buchs, Switzerland) and using 3-pyrineboronic acid (Aldrich, Buchs, Switzerland).
  • Example 1h The title compound is prepared in a similar manner as described in Example 1 by reacting 2-[4-(8-bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile (Example 1h ) with iodoethane (Fluka, Buchs, Switzerland) and using 3-pyridineboronic acid.
  • Example 57a The title compound is prepared in a similar manner as described in Example 1 using 3-fluoro-4-(4-methanesulfonyl-piperazin-1-yl)-phenylamine (Example 57a ) and 3-quinolineboronic acid.
  • Title compound: ES-MS: 583.5 (M+H) + ; analytical HPLC: t ret 4.12 minutes (Grad 2).
  • Example 57b The title compound is prepared in a similar manner as described in Example 14a using 1-(2-fluoro-4-nitro-phenyl)-4-methanesulfonyl-piperazine (Example 57b ).
  • Title compound: ES-MS: 274.3 (M+H) + ; analytical HPLC: t ret 3.50 minutes (Grad 2).
  • Example 59a The title compound is prepared in a similar manner described in Example 1 using 4-(4-amino-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Example 59a ) and 3-quinolineboronic acid.
  • the removal of the tert-butoxycarbonyl protecting group is performed by using 4 N HCl in dioxane following protocols known in the art ( The peptides, Vol. 3; ed. Edhard Gross and Johannes Meienhofer, Academic Press, New York ).
  • Title compound: ES-MS: 505.4 (M+H) + ; analytical HPLC: t ret 3.63 minutes (Grad 2).
  • Example 14a The title compound is obtained as described in Example 14a using 4-(2-fluoro-4-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (Example 59b ).
  • Title compound: ES-MS: 296.3 (M+H) + ; analytical HPLC: t ret 4.18 minutes (Grad 2).
  • Example 63a The title compound is obtained as described in Example 1 using (6-bromo-3-nitro-quinolin-4-yl)-[2-chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-amine (Example 63a ) and 3-quinolineboronic acid.
  • Title compound: ES-MS: 535.4 (M+H) + ; analytical HPLC: t ret 3.93 minutes (Grad 2).
  • Example 65a The title compound is obtained as described in Example 1 using 3-chloro-4-(4-methyl-piperazin-1-yl)-phenylamine (Example 65a ) and 3-quinolineboronic acid.
  • Title compound: ES-MS: 536.4 (M+H) + ; analytical HPLC: t ret 3.78 minutes (Grad 2).
  • Example 68a The title compound is obtained as described in Example 1 using 4-imidazol-1-yl-2-methylphenylamine (Example 68a ) and 3-quinolineboronic acid.
  • Title compound: ES-MS: 483.4 (M+H) + ; analytical HPLC: t ret 3.78 minutes (Grad 2).
  • Example 69a The title compound is obtained as described in Example 1 using 4-pyrazol-1-yl-phenylamine (Example 69a ) and 3-quinolineboronic acid.
  • Title compound: ES-MS: 469.4 (M+H) + ; analytical HPLC: t ret 4.18 minutes (Grad 2).
  • Example 71a The title compound is obtained as described in Example 1 using 4-[1,2,4]triazol-1-yl-phenylamine (Example 71a ) and 3-quinolineboronic acid.
  • Title compound: ES-MS: 470.3 (M+H) + ; analytical HPLC: t ret 3.99 minutes (Grad 2).
  • Example 73a The title compound is obtained as described in Example 1 using 4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-phenylamine (Example 73a ) and 3-quinolineboronic acid.
  • Title compound: ES-MS: 569.5 (M+H) + ; analytical HPLC: t ret 4.08 minutes (Grad 2).
  • Example 75a The title compound is obtained as described in Example 1 using 4-(4-amino-2-chlorophenyl)-piperazine-1-carboxylic acid tert-butyl ester (Example 75a ) and 3-quinolineboronic acid and removal of the tert-butoxycarbonyl protecting group in a similar manner as described in Example 59 .
  • Title compound: ES-MS: 521.4 (M+H) + ; analytical HPLC: t ret 3.68 minutes (Grad 2).
  • Example 75b The title compound is obtained as described in Example 1e using 2-chloro-4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Example 75b) as starting material.
  • Title compound: ES-MS: 312.2, 314.3 (M+H) + ; analytical HPLC: t ret 4.58 minutes (Grad 2).
  • Example 84a The title compound is obtained as described in Example 1 using 4-(4-amino-2-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Example 84a).
  • Title compound: Title compound: ES-MS: 555.0 (M+H) + ; analytical HPLC: t ret 3.86 minutes (Grad 2).
  • Example 84b The title compound is obtained as described in Example 1e using 4-(4-nitro-2-trifluoromethylphenyl)-piperazine-1-carboxylic acid tert-butyl ester (Example 84b ) as starting material.
  • Title compound: ES-MS: 346.2 (M+H) + ; analytical HPLC: t ret 4.95 minutes (Grad 2).
  • Example 89a The title compound is obtained as described in Example 1 using 4-(4-amino-2-chlorophenyl)-2,6- cis -dimethyl-piperazine-1-carboxylic acid tert-butyl ester (Example 89a ) and 3-pyridineboronic acid and removal of the tert-butoxycarbonyl protecting group in a similar manner as described in Example 59 .
  • Title compound: ES-MS: 499 (M+H) + ; analytical HPLC: t ret 2.24 minutes (Grad 1).
  • Example 89b The title compound is obtained in a similar manner as described in Example 1e starting with 4-(2-chloro-4-nitro-phenyl)-2,6- cis -dimethyl-piperazine-1-carboxylic acid tert-butyl ester (Example 89b ).
  • Title compound: ES-MS: 340 (M+H) + ; analytical HPLC: t ret 3.35 minutes (Grad 1).
  • Example 93a The title compound is obtained in a similar manner as described in Example 1 using 3-chloro-4-(4-isopropyl-piperazin-1-yl)-phenylamine (Example 93a ) and 3-pyridineboronic acid.
  • Title compound: ES-MS: 513 (M+H) + ; analytical HPLC: t ret 2.32 minutes (Grad 1).
  • Example 93b The title compound is obtained in a similar manner as described in Example 1e using 1-(2-Chloro-4-nitro-phenyl)-4-isopropyl-piperazine (Example 93b ).
  • Title compound: ES-MS: 254 (M+H) + ; analytical HPLC: t ret 1.80 minutes (Grad 1).
  • Example 93a The title compound is obtained in a similar manner as described in Example 1 using 3-chloro-4-(4-isopropyl-piperazin-1-yl)-phenylamine (Example 93a ) and 3-quinolineboronic acid.
  • Title compound: ES-MS: 563 (M+H) + ; analytical HPLC: t ret 2.68 minutes (Grad 1).
  • Example 95a The title compound is obtained in a similar manner as described in Example 1 using 4-(4-amino-2-trifluoromethyl-phenyl)-2,6- cis -dimethyl-piperazine-1-carboxylic acid tert-butyl ester (Example 95a ) and 3-pyridineboronic acid and removal of the tert-butoxycarbonyl protecting group in a similar manner as described in Example 59 .
  • Title compound: ES-MS: 533 (M+H) + ; analytical HPLC: t ret 2.37 minutes (Grad 1).
  • Example 95b The title compound is obtained in a similar manner as described in Example 1e starting with 4-(4-nitro-2-trifluoromethyl-phenyl)-2,6- cis -dimethyl-piperazine-1-carboxylic acid tert-butyl ester (Example 95b ).
  • Title compound: ES-MS: 374 (M+H) + ; analytical HPLC: t ret 3.79 minutes (Grad 1).
  • Example 89c The title compound is obtained in a similar manner as described in Example 89b starting with cis -3,5-Dimethyl-1-(4-nitro-2-trifluoromethyl-phenyl)-piperazine (Example 89c ).
  • Title compound: ES-MS: 404 (M+H) + ; analytical HPLC: t ret 4.76 minutes (Grad 1).
  • Example 95a The title compound is obtained in a similar manner as described in Example 1 using 4-(4-amino-2-trifluoromethyl-phenyl)-2,6- cis -dimethyl-piperazine-1-carboxylic acid tert-butyl ester (Example 95a ) and 3-quinolineboronic acid and removal of the tert-butoxycarbonyl protecting group in a similar manner as described in Example 59 .
  • Title compound: ES-MS: 583 (M+H) + ; analytical HPLC: t ret 2.71 minutes (Grad 1).
  • Example 97a The title compound is obtained in a similar manner as described in Example 1 using 4-(4-ethyl-piperazin-1-yl)-3-trifluoromethyl-phenylamine (Example 97a ) and 3-pyridineboronic acid.
  • Title compound: ES-MS: 533 (M+H) + ; analytical HPLC: t ret 2.38 minutes (Grad 1).
  • Example 97a The title compound is obtained in a similar manner as described in Example 1 using 4-(4-ethyl-piperazin-1-yl)-3-trifluoromethyl-phenylamine (Example 97a ) and 3-quinolineboronic acid.
  • Title compound: ES-MS: 583 (M+H) + ; analytical HPLC: t ret 2.73 minutes (Grad 1).
  • Example 99a The title compound is obtained in a similar manner as described in Example 1 using 4-(4-isopropyl-piperazin-1-yl)-3-trifluoromethyl-phenylamine (Example 99a ) and 3-pyridineboronic acid.
  • Title compound: ES-MS: 547 (M+H) + ; analytical HPLC: t ret 2.45 minutes (Grad 1).
  • Example 99a The title compound is obtained in a similar manner as described in Example 1 using 4-(4-isopropyl-piperazin-1-yl)-3-trifluoromethyl-phenylamine (Example 99a ) and 3-quinolineboronic acid.
  • Title compound: ES-MS: 597 (M+H) + ; analytical HPLC: t ret 2.82 minutes (Grad 1).
  • Example 104a The title compound is obtained in a similar manner as described in Example 1 using 3-chloro-4-imidazol-1-yl-phenylamine (Example 104a ) and 3-pyridineboronic acid.
  • Title compound: ES-MS: 453 (M+H) + ; analytical HPLC: t ret 2.09 minutes (Grad 1).
  • Example 104b The title compound is obtained in a similar manner as described in Example 1e starting with 1-(2-chloro-4-nitro-phenyl)-1H-imidazole (Example 104b ).
  • Title compound: ES-MS: 194 (M+H) + ; analytical HPLC: t ret 1.84 minutes (Grad 1).
  • Example 104a The title compound is obtained in a similar manner as described in Example 1 using 3-chloro-4-imidazol-1-yl-phenylamine (Example 104a ) and 3-quinolineboronic acid.
  • Title compound: ES-MS: 503 (M+H) + ; analytical HPLC: t ret 2.44 minutes (Grad 1).
  • Example 109d The title compound is obtained in a similar manner as described in Example 1 using 2-[4-(8-bromo-3-methyl-2-oxo-5-oxy-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methylpropionitrile (Example 109d) and 3-quinolineboronic acid.
  • Title compound: ES-MS: 486 (M + H) + ; analytical HPLC: t ret 3.14 minutes (Grad 1).
  • Example 110a The title compound is obtained in a similar manner as described in Example 1 using 1-(4-amino-phenyl)-cyclopropanecarbonitrile (Example 110a ) and 3-pyridineboronic acid.
  • Title compound: ES-MS: 418 (M+H) + ; analytical HPLC: t ret 3.82 minutes (Grad 2).
  • Example 110a The title compound is obtained in a similar manner as described in Example 1 using 1-(4-amino-phenyl)-cyclopropanecarbonitrile (Example 110a ) and 3-quinolineboronic acid.
  • Title compound: ES-MS: 468 (M+H) + ; analytical HPLC: t ret 4.14 minutes (Grad 2).
  • Example 110a The title compound is obtained in a similar manner as described in Example 1 using 1-(4-amino-phenyl)-cyclopropanecarbonitrile (Example 110a ) and 2-methoxy-5-pyridineboronic acid.
  • Title compound: ES-MS: 448.5 (M+H) + ; analytical HPLC: t ret 4.42 minutes (Grad 2).
  • Example 89 The title compound is obtained in a similar manner as described in Example 89 using 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and removal of the tert-butoxycarbonyl protecting group in a similar manner as described in Example 59 .
  • Title compound: ES-MS: 529 (M+H) + ; analytical HPLC: t ret 2.40 minutes (Grad 1).
  • Example 95a The title compound is obtained in a similar manner as described in Example 1 using 4-(4-amino-2-trifluoromethyl-phenyl)-2,6- cis -dimethyl-piperazine-1-carboxylic acid tert-butyl ester (Example 95a ) and 2-methoxy-5-pyridineboronic acid and removal of the tert-butoxycarbonyl protecting group in a similar manner as described in Example 59 .
  • Title compound: ES-MS: 563 (M+H) + ; analytical HPLC: t ret 2.76 minutes (Grad 1).
  • Example 95a The title compound is obtained in a similar manner as described in Example 1 using 4-(4-amino-2-trifluoromethyl-phenyl)-2,6- cis -dimethyl-piperazine-1-carboxylic acid tert-butyl ester (Example 95a ) and 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and removal of the tert-butoxycarbonyl protecting group in a similar manner as described in Example 59 .
  • Title compound: ES-MS: 563 (M+H) + ; analytical HPLC: t ret 2.50 minutes (Grad 1).
  • Example 128a The title compound is obtained as described in Example 1 using 4-[1,2,4]triazol-1-yl-3-trifluoromethylphenylamine (Example 128a ).
  • Title compound: ES-MS: 488 (M+H) + ; analytical HPLC: t ret 3.72 minutes (Grad 2).
  • Example 71a The title compound is obtained in a similar manner as Example 71a using 1-fluoro-4-nitro-2-trifluoromethyl-benzene (Aldrich, Buchs, Switzerland) and 1,2,4-triazole (Fluka, Buchs, Switzerland).
  • Title compound: ES-MS: 229 (M+H) + ; analytical HPLC: t ret 4.14 minutes (Grad 2).
  • Example 137a The title compound is obtained as described in Example 1 using 4-pyrazol-1-yl-3-trifluoromethyl-phenylamine (Example 137a ).
  • Title compound: ES-MS: 487 (M+H) + ; analytical HPLC: t ret 3.92 minutes (Grad 2).
  • Example 71a The title compound is obtained in a similar manner as Example 71a using 1-fluoro-4-nitro-2-trifluoromethyl-benzene (Aldrich, Buchs, Switzerland) and pyrazole (Fluka, Buchs, Switzerland).
  • Title compound: ES-MS: 228 (M+H) + ; analytical HPLC: t ret 4.58 minutes (Grad 2).
  • Example 142a The title compound is obtained in a similar manner as described in Example 1 starting with 3-chloro-4-[1,2,4]triazol-1-yl-phenylamine (Example 142a ).
  • Title compound: ES-MS: 454 (M+H) + ; analytical HPLC: t ret 2.28 minutes (Grad 1).
  • Example 144a The title compound is obtained as described in Example 1 using 4-pyrazol-1-yl-3-trifluoromethyl-phenylamine (Example 144a ).
  • Title compound: ES-MS: 487 (M+H) + ; analytical HPLC: t ret 3.54 minutes (Grad 2).
  • Example 138a The title compound is obtained in a similar manner as Example 138a using imidazole.
  • Title compound: ES-MS: 228 (M+H) + ; analytical HPLC: t ret 3.73 minutes (Grad 2).
  • Example 148a The title compound is obtained in a similar manner as described in Example 1 starting with 4-[1,2,4]Triazol-1-ylmethyl-phenylamine (Example 148a ).
  • Title compound: ES-MS: 434 (M+H) + ; analytical HPLC: t ret 2.13 minutes (Grad 1).
  • Example 148b The title compound is obtained in a similar manner as described in Example 1e starting with 1-(4-nitro-benzyl)-1H-[1,2,4]triazole (Example 148b ).
  • Title compound: ES-MS: 175 (M+H) + ; analytical HPLC: t ret minutes (Grad 2).
  • Example 150a The title compound is obtained in a similar manner as described in Example 1 starting with 4-imidazol-1-ylmethyl-phenylamine (Example 150a ).
  • Title compound: ES-MS: 433 (M+H) + ; analytical HPLC: t ret 1.96 minutes (Grad 1).
  • 4-toluenesulfonic acid salts are prepared in a stoichiometric ratio of 1:1 following standard reaction conditions in analogy to or according to methods that are known in the art: 152-1) 4-Toluenesulfonic acid 2-methyl-2-[4-(3-methyl-2-oxo-8-pyridin-4-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile salt; 152-2) 4-Toluenesulfonic acid 2-methyl-2-[4-(3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrife salt; 152-3) 4-Toluenesulfonic acid 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo
  • maleic acid salts are prepared in a stoichiometric ratio of 1:1 following standard reaction conditions in analogy to or according to methods that are known in the art.
  • 153-1) Maleic acid 2-methyl-2- ⁇ 4-[3-methyl-2-oxo-8-(6-piperazin-1-yl-pyridin-3-yl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-phenyl ⁇ -propionitrile salt; 153-2) Maleic acid 1-(3-fluoro-4-piperazin-1-yl-phenyl)-3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one salt; 153-3) Maleic acid 1-(3-fluoro-4-piperazin-1-yl-phenyl)-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one salt; 153-
  • Example 154 Soft capsules
  • Preparation process The pulverized active ingredient is suspended in Lauroglykol® (propylene glycol laurate, Gattefossé S.A., Saint Priest, France) and ground in a wet pulverizer to produce a particle size of about 1 to 3 ⁇ m. 0.419 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine.
  • Lauroglykol® propylene glycol laurate, Gattefossé S.A., Saint Priest, France

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Abstract

L'invention se rapporte à de nouveaux composés organiques représentés par la formule (I), à des procédés de préparation associés, à leur application dans un procédé de traitement du corps humain ou animal, à leur utilisation seule ou combinée avec un ou plusieurs autres composés pharmaceutiquement actifs pour le traitement d'une maladie inflammatoire ou des voies respiratoires obstructive, telle que l'asthme, les troubles généralement associés à une transplantation, ou une maladie proliférante, telle une tumeur.

Claims (12)

  1. Composé 2-méthyl-2-[4-(3-méthyl-2-oxo-8-quinoléin-3-yl-2,3-dihydro-imidazo[4,5-c]quinoléin-1-yl)-phényl]-propionitrile.
  2. Sel du composé selon la revendication 1 acceptable sur le plan pharmaceutique.
  3. Sel d'acide 4-toluènesulfonique du 2-méthyl-2-[4-(3-méthyl-2-oxo-8-quinoléin-3-yl-2,3-dihydro-imidazo[4,5-c]quinoléin-1-yl)-phényl]-propionitrile.
  4. Composé de formule I selon l'une quelconque des revendications 1, 2 ou 3, à utiliser en tant qu'agent pharmaceutique.
  5. Utilisation d'un composé selon l'une quelconque des revendications 1, 2 ou 3, pour la préparation d'un médicament destiné au traitement d'une maladie proliférative, d'une maladie inflammatoire ou d'une maladie respiratoire obstructive.
  6. Utilisation selon la revendication 5, dans laquelle la maladie proliférative est une maladie de type tumeur solide.
  7. Composé selon l'une quelconque des revendications 1, 2 ou 3, pour une utilisation dans le traitement d'une maladie proliférative, d'une maladie inflammatoire ou d'une maladie respiratoire obstructive.
  8. Composé à utiliser dans le traitement d'une maladie selon la revendication 7, où la maladie proliférative est une maladie de type tumeur solide.
  9. Préparation pharmaceutique comprenant un composé selon l'une quelconque des revendications 1, 2 ou 3, et au moins un excipient acceptable sur le plan pharmaceutique.
  10. Composé selon la revendication 1, 2 ou 3, à utiliser en combinaison avec un ou plusieurs autres composés antiprolifératifs dans la thérapie d'une tumeur.
  11. Composé selon la revendication 10, dans lequel le ou les composés antiprolifératifs est/sont sélectionné(s) parmi des inhibiteurs de l'aromatase, des anti-oestrogènes, des inhibiteurs de la topo-isomérase I, des inhibiteurs de la topo-isomérase II, des composés actifs sur les microtubules, des composés d'alkylation, des inhibiteurs de l'histone désacétylase, des composés qui induisent des processus de différenciation cellulaire, des inhibiteurs de la cyclooxygénase, des inhibiteurs de MMP, des inhibiteurs de mTOR, des antimétabolites antinéoplasiques, des composés de platine, des composés qui ciblent/réduisent l'activité d'une protéine ou d'une lipide kinase et d'autres composés antiangiogéniques, des composés qui ciblent, réduisent ou inhibent l'activité d'une protéine ou d'une lipide phosphatase, des agonistes de la gonadoréline, des anti-androgènes, des inhibiteurs de la méthionine aminopeptidase, des bisphosphonates, des modificateurs de la réponse biologique, des anticorps antiprolifératifs, des inhibiteurs de l'héparanase, des inhibiteurs des isoformes oncogènes de Ras, des inhibiteurs de la télomérase, des inhibiteurs du protéasome, des composés utilisés dans le traitement de malignités hématologiques, des composés qui ciblent, réduisent ou inhibent l'activité de Flt-3, des inhibiteurs de la Hsp90, des inhibiteurs de la protéine de fuseau kinésine ou des inhibiteurs de MEK.
  12. Composé selon la revendication 1, 2 ou 3, à utiliser en combinaison avec l'administration d'hormones ou des rayonnements.
EP06753710A 2005-05-20 2006-05-18 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoléin-3-yl-2,3-dihydro-imidazo [4,5-c] quinoléinyl)-phenyl]propionitrile en tant qu'inhibiteur de kinase lipidique Active EP1888578B8 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
DK10175369.7T DK2292617T3 (da) 2005-05-20 2006-05-18 1,3-Dihydro-imidazo[4,5-c]quinolin-2-ones som lipid kinase og/eller pi3-kinase-inhibitorer
PL06753710T PL1888578T3 (pl) 2005-05-20 2006-05-18 2-Metylo-2-[4-(3-metylo-2-okso-8-chinolin-3-ylo-2,3-dihydro-imidazo [4,5-c]chinolinylo)-fenylo]propionitryl jako inhibitor kinaz lipidowych
EP10175375A EP2270008B8 (fr) 2005-05-20 2006-05-18 8-Hétéroaryl-3-alkyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-ones comme inhibiteurs des PI-3 kinases
PL10175375T PL2270008T3 (pl) 2005-05-20 2006-05-18 8-Heteroarylo-3-alkilo-1,3-dihydro-imidazo[4,5-c]chinolin-2-ony jako inhibitory kinaz PI-3
EP10175369A EP2292617B1 (fr) 2005-05-20 2006-05-18 Dérivés de 1,3-dihydro-imidazo[4,5-c]quinolin-2-one comme inhibiteurs de kinase lipidique et/ou de kinase pi3
SI200631230T SI1888578T1 (sl) 2005-05-20 2006-05-18 2-metil-2-(4-(3-metil-2-okso-8-kinolin-3-il-2,3-dihidro-imidazo(4,5-c) kinolinil)-fenil)propionitril kot lipid kinazni inhibitor
DK10175375.4T DK2270008T3 (da) 2005-05-20 2006-05-18 8-Heteroaryl-3-alkyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-oner som PI-3-kinaseinhibitorer
CY20121100169T CY1112369T1 (el) 2005-05-20 2012-02-17 2-μεθυλο-2-[4-(3-μεθυλο-2-οξο-8-κινολιν-3-υλο-2,3-διϋδρο-ιμιδαζο[4,5-c]κινολινυλο)-φαινυλο]προπιονιτριλιο ως αναστολεας λιπιδικης κινασης

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GBGB0510390.8A GB0510390D0 (en) 2005-05-20 2005-05-20 Organic compounds
PCT/EP2006/004725 WO2006122806A2 (fr) 2005-05-20 2006-05-18 Imidazoquinolines utilises en tant qu'inhibiteurs de kinase lipidique

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EP10175375A Division EP2270008B8 (fr) 2005-05-20 2006-05-18 8-Hétéroaryl-3-alkyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-ones comme inhibiteurs des PI-3 kinases
EP10175375.4 Division-Into 2010-09-06
EP10175369.7 Division-Into 2010-09-06

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EP1888578A2 EP1888578A2 (fr) 2008-02-20
EP1888578B1 EP1888578B1 (fr) 2011-11-30
EP1888578B9 true EP1888578B9 (fr) 2012-04-25
EP1888578B8 EP1888578B8 (fr) 2013-04-03

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EP06753710A Active EP1888578B8 (fr) 2005-05-20 2006-05-18 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoléin-3-yl-2,3-dihydro-imidazo [4,5-c] quinoléinyl)-phenyl]propionitrile en tant qu'inhibiteur de kinase lipidique
EP10175375A Active EP2270008B8 (fr) 2005-05-20 2006-05-18 8-Hétéroaryl-3-alkyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-ones comme inhibiteurs des PI-3 kinases
EP10175369A Not-in-force EP2292617B1 (fr) 2005-05-20 2006-05-18 Dérivés de 1,3-dihydro-imidazo[4,5-c]quinolin-2-one comme inhibiteurs de kinase lipidique et/ou de kinase pi3

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EP10175369A Not-in-force EP2292617B1 (fr) 2005-05-20 2006-05-18 Dérivés de 1,3-dihydro-imidazo[4,5-c]quinolin-2-one comme inhibiteurs de kinase lipidique et/ou de kinase pi3

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US20080269846A1 (en) * 2003-03-14 2008-10-30 Light Sciences Oncology, Inc. Device for treatment of blood vessels using light
US10376711B2 (en) * 2003-03-14 2019-08-13 Light Sciences Oncology Inc. Light generating guide wire for intravascular use
AR045261A1 (es) 2003-08-12 2005-10-19 3M Innovative Properties Co Compuestos que contienen imidazo quinolina o imidazo piridina sustituidos; composiciones farmaceuticas que los contienen y su uso en la preparacion de medicamentos inmunomoduladores
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